CA1183136A - Nonaprenylamine derivatives - Google Patents
Nonaprenylamine derivativesInfo
- Publication number
- CA1183136A CA1183136A CA000376058A CA376058A CA1183136A CA 1183136 A CA1183136 A CA 1183136A CA 000376058 A CA000376058 A CA 000376058A CA 376058 A CA376058 A CA 376058A CA 1183136 A CA1183136 A CA 1183136A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
ABSTRACT
New pharmaceutically active nonaprenylamine deri-vatives having the general formula:
(I) wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the group R being unsubstituted or substituted with a hydrogen atom or a hydroxy lower alkyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharma-ceutically acceptable acid addition salts thereof, are prepared by converting nonaprenol of the formula:
(II) into a corresponding halide or aryl sulfonic acid ester which is thereafter reacted with a heterocyclic compound containing at least one secondary amino group and having the general formula:
(III) wherein R has the aforesaid meaning, in the presence or absence of a base, when a pharmaceutically acceptable acid addition salt is desired, the nonaprenylamine derivative of the formula (I) thus obtained is further reacted with a pharmaceutically acceptable acid to provide the desired salt.
The compounds of the invention are useful for controlling virus infection of vertebrate animals.
New pharmaceutically active nonaprenylamine deri-vatives having the general formula:
(I) wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the group R being unsubstituted or substituted with a hydrogen atom or a hydroxy lower alkyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharma-ceutically acceptable acid addition salts thereof, are prepared by converting nonaprenol of the formula:
(II) into a corresponding halide or aryl sulfonic acid ester which is thereafter reacted with a heterocyclic compound containing at least one secondary amino group and having the general formula:
(III) wherein R has the aforesaid meaning, in the presence or absence of a base, when a pharmaceutically acceptable acid addition salt is desired, the nonaprenylamine derivative of the formula (I) thus obtained is further reacted with a pharmaceutically acceptable acid to provide the desired salt.
The compounds of the invention are useful for controlling virus infection of vertebrate animals.
Description
3~
This invention relates to new pharmaceutically active nonaprenylamine derivatives, their pharmaceutically acceptable acid addition salts as well as to a process for their preparation. The new compounds with which the invention is concerned are useful for controlling virus infection of vertebrate animals.
There are ]~own heretofore various substances, which have been found to have preventive or alleviative effects on diseases caused by virus whose host is a verte-braté animal, or which have been recognized to be capableof alleviating symptoms of the diseases by significantly enhancing antibody activity in the animal. Antivirotics reported so far include interferon, substances capable of inducing interferon, i.e. inducers (interferon inducers), amantadine hydrochloride or synthetic substances, such as methysazone, which directly exert inhibitory effect on the virus propagation. Interferon is glycoprotein having anti-viral and antitumor activity, the glycoprotein being pro-duced in situ by cells of a vertebrate animal when the cells are infected with virus, and is effective against a very wide range of virus-infected diseasesu Known inducers, which induce interferon in vertebrate animals by a process other than the virus infection, include natural high molecular substances such as double chain ribonucleic acid of bacte-riophage of a certain species, or synthetic high molecular substances such as double chain ribonucleic acid, typical o~
which is polyinosinic acid-polycytidylic acid, or low mole-cular inducers such as tyrolone.
In the production of interferon, however, there is involved a problem how to carry out the purification thereof, and in fact no economical process for the production
This invention relates to new pharmaceutically active nonaprenylamine derivatives, their pharmaceutically acceptable acid addition salts as well as to a process for their preparation. The new compounds with which the invention is concerned are useful for controlling virus infection of vertebrate animals.
There are ]~own heretofore various substances, which have been found to have preventive or alleviative effects on diseases caused by virus whose host is a verte-braté animal, or which have been recognized to be capableof alleviating symptoms of the diseases by significantly enhancing antibody activity in the animal. Antivirotics reported so far include interferon, substances capable of inducing interferon, i.e. inducers (interferon inducers), amantadine hydrochloride or synthetic substances, such as methysazone, which directly exert inhibitory effect on the virus propagation. Interferon is glycoprotein having anti-viral and antitumor activity, the glycoprotein being pro-duced in situ by cells of a vertebrate animal when the cells are infected with virus, and is effective against a very wide range of virus-infected diseasesu Known inducers, which induce interferon in vertebrate animals by a process other than the virus infection, include natural high molecular substances such as double chain ribonucleic acid of bacte-riophage of a certain species, or synthetic high molecular substances such as double chain ribonucleic acid, typical o~
which is polyinosinic acid-polycytidylic acid, or low mole-cular inducers such as tyrolone.
In the production of interferon, however, there is involved a problem how to carry out the purification thereof, and in fact no economical process for the production
- 2 - ~
3~
thereof hag not been established yet. On the other hand, conventional interfexon inducers have not been put to prac-tical use mainly because of toxicity thereof. Synthetic antiviral agents which directly exert inhibitory effect on the virus propaga ion, which are commercially available at present, have a rather narrow range of virus-infected diseases which are curable by administration of said agent, and thus the advent of novel synthetic antiviral agents is earnestly desired. Taking such c:ircumstances into conside-ration, th~ present inventors extensively conducted studies in finding compounds capable of producing interferon of high potency and, moreover, having antiviral activity on the biological level, and as a result they have eventually found that the new nonaprenylamine derivatives of the following general formula lI) and the pharmaceutically acceptable acid addition salts thereof show excellent interferon inducing ability and, at the same time, demonstrate excellent antivi-ral and antitumor activity even in the biological test, and are thus use~ul as medicaments.
According to one aspect of the present invention, there is thus provided a new class of nonaprenylamine derivatives represented by the following general ~ormula-H ( - CH2-1=CH-CH2 )9 -- ~ (I) wherein R is an atomic grouping capable of forming together with the adjacent nitrogen atom, a 5- or 6-membered hetero~
cyclic ring which may contain further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the group R being unsubstituted or substituted with a hydrogen atom or a hydroxy lower alkyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharmaceutically acceptahle acid addition salts thereof.
3~
The nonaprenylamine derivatives of the general for-mula (I) and their pharmaceutically acceptable acid addition salts may be prepared in accordance with known procedures for amine synthesis, starting from nonaprenol (solanesol) having the formula:
fH3 H --t~ CH2-C=C~-c~I2 - ~ ~ OH (II) According to a further aspect of the invention, there is thus provided a process for the preparation of the nonaprenylamine derivatives having the general formula (I), which comprises:
a) converting nonaprenol of the formula:
fH3 H -~- CH2-C=CH-CH2 - ~ OH (II) into a corresponding halide or aryl sulfonic acid ester which is thereafter reacted with a heterocyclic compound containing at least one secondary amino group and having the general formula:
H~ ~ (III~
wherein R has the aforesai.d meaning, in the presence or absence of a base, to obtain the desired nonaprenylamine derivative of the formula (I); and b) when a pharmaceut.ically acceptable acid aadition salt is desired, further reacting the nonaprenylamine deri-vative of the formula (I) thus obtained with a pharmaceuti-cally acceptable acid to provide the desired salt.
The pharmaceutically acceptable acid addition salt thus obtained can be isolated by crystallizing the salt out of the solut.ion by evaporation or by other means to recover the same~ The acid addition salts suitable fol- use as medi-~cines include, for example, those formed with hydrochloric -. ) 4 3~
ac:id, acetic acid, c.itric aci.d, fumaric acid, lactic acid and the like~
The compounds or the general formula (I~ and their pharmaceutically acceptable acid addition salts are illus-trated hereinbelow with reference to preparative examples.
N-solanesylpiperazine di.hydrochloride CH
H ~ CH2-1=CEI-CH2- ~ N N-H 2HCl To a mixture of piperazine (9~3 g.), ethanol (50 ml) and isopropylether (30 ml) a solution of solanesyl bromide (10 g.) in isopropylether (20 ml) was added dropwise at room temperature for ~.5 hours with stirring, which was continued for further 1 hour, followed by standing overnight. To the resulting reaction mixture a solution of sodium hydroxide ~4 g.) in water (20 ml) was dropwise added with ice-cooling and stirring and then extracted with isopropylether. The extr.act was washed successive~y with water and saturated saline, dried over with anhydrous sodium sulfate and th~n concentrated under reduced pressure. The residue (9.4 g.) was purified ~y column chromatogra~hy using silica gel (100 g.).
Elution was carried out with chloroform-methanol. The initiallly eluted fraction (7.3 g.) was dissolved in ethyl acetate (200 ml~, added with an ether solution containing 6N HCl to render it weakly acidic and then cooled. The crys-tallized mass was separated by filtration to recover N-s~lane-sylpiperazine dihydrochloride (5.1 g.), m.p. 137 - 140C.
Elementary analysis as C49H82N2 2HCl~3/2H20 showed the followi~go C/O_ ~O ~/O
Calcd. :73.64 10.973.51 Found :73.83 10.913.48 Prepara-tive Exc~mples 2 to ~
qlhe same procedures as in Example 1 were carried out for -the reac-tion of solanesyl bromide wi-th a hetero-cyclic derivative having secondary ~mino group thereby to produce~ the below-indicated compounds 9 the s-tructural ~ormula9 molecular f`ormula9 melting point and elementary analysis of which also are lis-tec~ in Table 1.
) o- t -~
i ~ cr r_ ~, ~ ~ U~
~rl ~ ~_ ~ O ~ ~
U~ O
J ~ ~ JO ~ O
~:i cr~ C- co ~ ~-.t.o a:
co g~ ~ t~
~ ~ ~ O
~1 ~ ~;' ~ O
Itd ~ t a' O ~0 I 3 t- t- t co a o ~ o ~ ~
O O C) ~O
E~ O ~i h :I
~15 o r-l ~;Sr-l V ~) ~S ~
~ ~; ~0i ~ 0;
~0 ~0 ~ CO t~ t Q~
V V V V V
E} ~3 U~ V~
i~
V
. ~
~ ~, i~ Ei ~ ~. o ~ ~ ~ Lr ~o C~
7~
3~L3~
Physiological effec-ts o~ the compounds o~ the present inven-tion are illus-trated below in detail.
(1) In-terferon inducing acti.vity tes-t Each tes-t compound suspended in water wi-th a surfactant waæ intraperi-toneally administered to each group consisting of 5 IaR ~emale mice weighing about 25 gO
~wen-ty hours af-ter adminis-tration9 blood was collec-ted ~rom -the mi.ce and serum was separated there~rom -to ob-tain a serum inter~eronO ~he following steps were taken in order to determine po-tency of the ser~m interfexon thus induced~ ~929 cells derived from mice and incubated previously in a monolayer was brought into con-tac-t with th~ test serum solution dilu-ted 10 times 5 incubated overnight at 379C in an incubator placed in carbon dioxide atmosphere and the dilu-te tes-t serum solu-tion was removed there~rom. ~hereafter9 the cells were inoculated wi-th vesicular stomatitis virus and placed on a tissue culture medium con~alning 1% agarO A~ter i.ncubation at 37C for 24 hours 9 the cells were dyed with neutral red solution diluted to an appropriate concen-tration to count -the number o~ plaques ~ormed thereon and thereby to calculate -the plaque inhibition rate in each of -the tes-t groups against a group to which no test compound had been administeredO
The plaque inhibition rate o~ each test compound is shown in ~able 2.
(2) E~ect on mice .infected with vaccinla virus Groups9 each conslsting of 10 ICR female mice wei.ghing about 15 g.9 were in-travenously injec-ted with 0.1 ml o~ a vaccinia virus (DIE strain) dilution through the vein of -tail at -the distance of 2 cm ~rom the root of the -tail. On the 8th day after -the inoGulation9 the number of lesions in form o~ smclll pocks on -the tai,l surface was counted after dyeing -t:he -tail with a solu-tion containing 1% fluorescein and 0.5U~o me-thylene blue. In this test 5 each test compound was aclministered in-t.ra-peritoneally to -the mice on -the day just before inoculation of -the virus9 where'by m-tivirus ac-tivi-ty o~ the -tes-t compound was evalua-ted in terms of inhibi-tion o~ tail lesions as calcu].a-ted in each -test group a,gainst a group to which no test compound had been administeredO
I'he rate of tail lesion inhibition of each -tes-t compound is sho~n in ~able 2~
~3) ~f~ect on mice in~ec-ted with in~luenza virus Groups9 each consisting of 10 ICR ~emale mice weighing about 25 gO were challenged by intralation of neblyzed influen~a virus A/PR-8. A solu-tion of each test compound in an aqueous solution containing a sur~actant was intraperitoneally administered to the mice 24 hours and 3 hours before the virus in~ection9 and 5 times every other day ~rom the second day after the infectionO ~he mice that survived 21 days a~ter -the challenge were regarded as survivors9 and survival rate was obtained according -to the following equationO
Number of survivors x 100 -- survival rate ~%) ~umber o~ mice treated 3~3~
o o a~
h ~-~
~ ~ O
o a H N t~
, ~ P
P~ ~ r~
.
o o~
0 ~i b ~ l o o ~rl Q~ a ,9 a td ~
~rl ~i C~l O o ~
h o O
g 0~ r-CO
~rl ~rl ~ t) ~i ~1 F4 ~.~
,_ ~ ~ O O
~q . ~ LS~
O r~ ~L
.
a~
1'' 8 O t ~ ~ p~
E~ ~ o ~ } g ~ 10 -3~
oxlcity In order to investiga-te acute -toxicity of tha compounds of the presen-t invention~ 50~0 lethal dose of each compound was ob-tained by using ddY male mice weighing 20 ~ 25 g. From the resul-ts shown in rl'able 37 i-t is understood that -the compounds had high safe-ty margin by in-traperi-toneal administrationO
~able 50~ ~ethal dose ~m ~ ~
Intravenously Intraperitoneally ~est com~ound administered administered N-~hydroxyethyl~i\T'- 150 ~500 solanesylpiperazine As is clear from the foregoing test results 9 the active ingredients of the present invention have interferon inducing activity in vivo and are low in toxicity with showing excellent antivixal activity. In the light of the fact tha-t the s-tric-t correlation of interleron activity with the individual antiviral ac-tivities is not always observed for the present ingredients 9 there is considered also a possibili-ty that the antivirus activities of said ingredients a-t biological level are concerned not only in int~rferon but also in other defensive mechanism of hos-t. 1'here are known various human diseases caused by virus 9 such as herpes-in~ecl;ed diseases (e.g~ herpes simplex)7 influenza7 measles and 1;he like. Accordingly) when the active ingredients of the present invention are used for 3~
prevention ancl treatment of viru,s--infected diseases9 they are adminis-tered to patien-ts by such -techniques involving oral 9 inhalant 9 or the like adminis-tration as well as subcu-taneous 3 intramascular and in-travenous injecti.onO
According to the condition of patient such as age 9 syrQp-tom and rou-te by which the ingredieYl-t is adminls-tered7 the acti~e ingredien-t of the presen-t invention is used in a dose of 0~5 - 20 mg/kg 9 pre~erably 3 - 5 mg/kg several -times (2 - 4 times) per dayO
~he active ingredients of the present invention can be for-mula-ted into composi-tions for medication5 for example 9 table-ts9 capsules9 granules 9 powder9 liquid prepara-tion for oral use9 eye lotions9 suppositories 9 ointments 7 in jections and the like9 according to any conventional method~
~ hen the present active ing-redients are orally administered9 they may be formulated into tablets 7 capsules9 granules ox powderO ~hese solid preparations for oral use may con-tain commonly used excipients9 for example9 silicic anhydride9 metasilicic acid9 magnesium alginate9 s~yn-thetic aluminum silicate 9 lactose9 cane sugar9 corn starch9 microcrystalline cellulose9 hydroxy-propylated starch or glycine9 and the like 9 binders9 for example 9 gum arabic9 gelatin9 tragacanth9 hydroxypropyl cellulose or polyvinylpyrrolidone 9 lubricants9 for example9 magnesium steara-te 9 talc or silica9 disintegrating agents9 for example 9 potato starch and calcium carboxymethyl cellulose; or wetting agen-ts9 for example9 polye-thylene glycol9 sorbitan monooleate9 polyoxyethylene-hardened castor oil9 sodium laurylsulfateO In preparing soft ~3~3~
capsules9 in particular 9 t:he present active ingredien-ts may be formula-ted 'by dissolving or suspending them in polyethylene glyc.ol or common:ly used oily su'bs-tra-tes such as sesame oil 9 peanu-t oil9 gexm oil9 frac-tiona-ted coconut oil such as Miglyol ~ 9 or the like. Tabl~t or granule prepara-tion~ may 'be coated acc.orcling -to the usucll me-thod.
'Li.quid prepaxation for oral use may 'be in the ~orm o~ aqueous or oily emulsi.on or syrup9 or alter natively l~l the form of dry product which can be re-dissolved before use by means o~ a suita'ble vehicle~
~o these liquid preparations 7 there may be added commonly used additives9 for example 7 emulsi~ying aids such a,s sorbitol syrup9 methyl cellulose9 gelatin9 hydroxyethyl cellulose and the like9 or emulsi~iers9 ~or e~ample9 leci-'chin9 sorbitan monooleate9 polyoxyethylene hardened castor oil9 non~aqueous vehicles9 ~or example 9 fractionated coconu-t oil9 almond oil9 peanut oil and the like9 or antiseptics9 for e~ample me-thyl p~hydroxybenzoate9 propyl p~hydroxybenzoate or sorbic acidO ~ur-ther9 these prepara~
~0 tions f'or oral use may contain9 i~ necessary9 preservatives9 s-tabilizers and the like additivesO
In case where the present ac-tive ingredients are administered in the form of non~oral suppository9 they may be formulated according to the ordinary method using oleophi.lic substrates such as cacao oil or Witepsol ~ 9 or may be used in -the form o~ rectum capsule obtained by wrapping a mixture o~ polyethylene glycol9 sesame oil9 peanu-t oil9 germ oil9 fractionated coconut oil and the like in a gelatin sheet. ~he rectum capsule may be coated9 if necessary9 with waxy materials~
- l3 L 3~D
~ en the present active ingredien-ts are used in the form of injection9 -they may be formulated into prepara-tiol~s of oil solution7 emulsl~ied solution or aqueous solution9 and these solutions may contain commonly used emulsi~iers 9 s tabilizers or -the like additi~es.
Accorcling tc the met;hod of administra-tion9 the above-men-tioned compositions can con-tain the presen-t ac-tive ingredients in an amount o~ at least 1~o7 preferably 5 to 50~0 ~ he procedure of formulating -the present active ingredients into various preparations is illus-trated below with reference to Pharmaceutical :Exanples.
Pharmaceutical Example 1 Eard capsule preparations for oral use A mixture of 25 gO of N~~hydroxyethyl~N'~
solanesylpiperazine and 7.5 gO of pol~oxyethylene castor oil in acetone was mixed with 25 gO of silicic anhydride.
A~-ter evaporation of -the acetone 9 the mixture was mixed further with 5 g. of calcium carboæ~methylcellulose 9 5 gO
of corn starchg 705 gO of hydroxypropylcellulose and 20 gO
of microcrystalline cellulose 3 and 30 ml of water was added -there-to and kneaded to give a granular massO ~he mass was pelletized by means of a pelletizer (EC~ pelletter 25 o~ ~u ji Paudal ~o~7 Japan) equipped with l~o. 24 mesh (B.S.) screen to obtain granules. ~he granules were dried to less -than 5~o moisture content and screened with No. 16 mesh (B~S.) screenO ~he screene~ granules were capsuled by means of a capsule filling machine so as -to be contained in an amoun-t of 190 mg per capsule.
L .-3~
Pharmaceutical ~xample 2 Soft capsule preparationsfor oral use A homogeneous solution was prepared by mixing 50 g~ o~ N solanesylpiperazine dihydrochloride with 1~0 g.
of polyethylene glycol (Macrogol ~00). Separately9 a gela-tin solution was prepa~ecl which contained 93 g. o~
gelatin9 19 g. of` glycerine9 10 g. o~ D-sorbitol7 0.4 g, o~ ethyl p--hydroxybenzoate 9 Oo 2 gO of propyl p-hydroxy benzoa-te and 0.4 g. o~ titanium oxide and w.hich wa,s used as a capsule ~ilm ~oxmlng agent. ~he prs~iously ob-tained solution9 together with -the capsule film ~orming agentp was trea-ted with a manual -type ~la-t punching machine to obtain so~t capsules each having the contents of 180 mg.
Pharmaceutical Example 3 Injections A mixture of 5 gO of N~hydroxyethyl~N'~
solanesylpiperazine9 an appropriate amount of peanut oil and 1 g. o~ benzy.l alcohol was made a total volume of 100 cc by addition of peanut oil. The solution was portionwise poured in ~l amount of 1 cc under asepsis operation into an ampule which was then sealed.
Pharmaceutical Example 4 Injections A mi~ture o~ loO g. of N--solanesylpiperazine dihydrochloxide9 5.0 g. o~ Nikkol HC0-60 (a tradename) (hydrogenated castor oil polyoxyethylene--60 mols~ether)9 20 gO o~ propylene glycol, 10 g. o~ glycerol and 5.0 g.
of ethyl alcohQl was mlxed with 100 ml o~ distillsd wate~
and s-tirred. Under asepsis operation~ the solution was portionwise poured in an amolmt of 1.4 ml into an ampule which was then sealed.
thereof hag not been established yet. On the other hand, conventional interfexon inducers have not been put to prac-tical use mainly because of toxicity thereof. Synthetic antiviral agents which directly exert inhibitory effect on the virus propaga ion, which are commercially available at present, have a rather narrow range of virus-infected diseases which are curable by administration of said agent, and thus the advent of novel synthetic antiviral agents is earnestly desired. Taking such c:ircumstances into conside-ration, th~ present inventors extensively conducted studies in finding compounds capable of producing interferon of high potency and, moreover, having antiviral activity on the biological level, and as a result they have eventually found that the new nonaprenylamine derivatives of the following general formula lI) and the pharmaceutically acceptable acid addition salts thereof show excellent interferon inducing ability and, at the same time, demonstrate excellent antivi-ral and antitumor activity even in the biological test, and are thus use~ul as medicaments.
According to one aspect of the present invention, there is thus provided a new class of nonaprenylamine derivatives represented by the following general ~ormula-H ( - CH2-1=CH-CH2 )9 -- ~ (I) wherein R is an atomic grouping capable of forming together with the adjacent nitrogen atom, a 5- or 6-membered hetero~
cyclic ring which may contain further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the group R being unsubstituted or substituted with a hydrogen atom or a hydroxy lower alkyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharmaceutically acceptahle acid addition salts thereof.
3~
The nonaprenylamine derivatives of the general for-mula (I) and their pharmaceutically acceptable acid addition salts may be prepared in accordance with known procedures for amine synthesis, starting from nonaprenol (solanesol) having the formula:
fH3 H --t~ CH2-C=C~-c~I2 - ~ ~ OH (II) According to a further aspect of the invention, there is thus provided a process for the preparation of the nonaprenylamine derivatives having the general formula (I), which comprises:
a) converting nonaprenol of the formula:
fH3 H -~- CH2-C=CH-CH2 - ~ OH (II) into a corresponding halide or aryl sulfonic acid ester which is thereafter reacted with a heterocyclic compound containing at least one secondary amino group and having the general formula:
H~ ~ (III~
wherein R has the aforesai.d meaning, in the presence or absence of a base, to obtain the desired nonaprenylamine derivative of the formula (I); and b) when a pharmaceut.ically acceptable acid aadition salt is desired, further reacting the nonaprenylamine deri-vative of the formula (I) thus obtained with a pharmaceuti-cally acceptable acid to provide the desired salt.
The pharmaceutically acceptable acid addition salt thus obtained can be isolated by crystallizing the salt out of the solut.ion by evaporation or by other means to recover the same~ The acid addition salts suitable fol- use as medi-~cines include, for example, those formed with hydrochloric -. ) 4 3~
ac:id, acetic acid, c.itric aci.d, fumaric acid, lactic acid and the like~
The compounds or the general formula (I~ and their pharmaceutically acceptable acid addition salts are illus-trated hereinbelow with reference to preparative examples.
N-solanesylpiperazine di.hydrochloride CH
H ~ CH2-1=CEI-CH2- ~ N N-H 2HCl To a mixture of piperazine (9~3 g.), ethanol (50 ml) and isopropylether (30 ml) a solution of solanesyl bromide (10 g.) in isopropylether (20 ml) was added dropwise at room temperature for ~.5 hours with stirring, which was continued for further 1 hour, followed by standing overnight. To the resulting reaction mixture a solution of sodium hydroxide ~4 g.) in water (20 ml) was dropwise added with ice-cooling and stirring and then extracted with isopropylether. The extr.act was washed successive~y with water and saturated saline, dried over with anhydrous sodium sulfate and th~n concentrated under reduced pressure. The residue (9.4 g.) was purified ~y column chromatogra~hy using silica gel (100 g.).
Elution was carried out with chloroform-methanol. The initiallly eluted fraction (7.3 g.) was dissolved in ethyl acetate (200 ml~, added with an ether solution containing 6N HCl to render it weakly acidic and then cooled. The crys-tallized mass was separated by filtration to recover N-s~lane-sylpiperazine dihydrochloride (5.1 g.), m.p. 137 - 140C.
Elementary analysis as C49H82N2 2HCl~3/2H20 showed the followi~go C/O_ ~O ~/O
Calcd. :73.64 10.973.51 Found :73.83 10.913.48 Prepara-tive Exc~mples 2 to ~
qlhe same procedures as in Example 1 were carried out for -the reac-tion of solanesyl bromide wi-th a hetero-cyclic derivative having secondary ~mino group thereby to produce~ the below-indicated compounds 9 the s-tructural ~ormula9 molecular f`ormula9 melting point and elementary analysis of which also are lis-tec~ in Table 1.
) o- t -~
i ~ cr r_ ~, ~ ~ U~
~rl ~ ~_ ~ O ~ ~
U~ O
J ~ ~ JO ~ O
~:i cr~ C- co ~ ~-.t.o a:
co g~ ~ t~
~ ~ ~ O
~1 ~ ~;' ~ O
Itd ~ t a' O ~0 I 3 t- t- t co a o ~ o ~ ~
O O C) ~O
E~ O ~i h :I
~15 o r-l ~;Sr-l V ~) ~S ~
~ ~; ~0i ~ 0;
~0 ~0 ~ CO t~ t Q~
V V V V V
E} ~3 U~ V~
i~
V
. ~
~ ~, i~ Ei ~ ~. o ~ ~ ~ Lr ~o C~
7~
3~L3~
Physiological effec-ts o~ the compounds o~ the present inven-tion are illus-trated below in detail.
(1) In-terferon inducing acti.vity tes-t Each tes-t compound suspended in water wi-th a surfactant waæ intraperi-toneally administered to each group consisting of 5 IaR ~emale mice weighing about 25 gO
~wen-ty hours af-ter adminis-tration9 blood was collec-ted ~rom -the mi.ce and serum was separated there~rom -to ob-tain a serum inter~eronO ~he following steps were taken in order to determine po-tency of the ser~m interfexon thus induced~ ~929 cells derived from mice and incubated previously in a monolayer was brought into con-tac-t with th~ test serum solution dilu-ted 10 times 5 incubated overnight at 379C in an incubator placed in carbon dioxide atmosphere and the dilu-te tes-t serum solu-tion was removed there~rom. ~hereafter9 the cells were inoculated wi-th vesicular stomatitis virus and placed on a tissue culture medium con~alning 1% agarO A~ter i.ncubation at 37C for 24 hours 9 the cells were dyed with neutral red solution diluted to an appropriate concen-tration to count -the number o~ plaques ~ormed thereon and thereby to calculate -the plaque inhibition rate in each of -the tes-t groups against a group to which no test compound had been administeredO
The plaque inhibition rate o~ each test compound is shown in ~able 2.
(2) E~ect on mice .infected with vaccinla virus Groups9 each conslsting of 10 ICR female mice wei.ghing about 15 g.9 were in-travenously injec-ted with 0.1 ml o~ a vaccinia virus (DIE strain) dilution through the vein of -tail at -the distance of 2 cm ~rom the root of the -tail. On the 8th day after -the inoGulation9 the number of lesions in form o~ smclll pocks on -the tai,l surface was counted after dyeing -t:he -tail with a solu-tion containing 1% fluorescein and 0.5U~o me-thylene blue. In this test 5 each test compound was aclministered in-t.ra-peritoneally to -the mice on -the day just before inoculation of -the virus9 where'by m-tivirus ac-tivi-ty o~ the -tes-t compound was evalua-ted in terms of inhibi-tion o~ tail lesions as calcu].a-ted in each -test group a,gainst a group to which no test compound had been administeredO
I'he rate of tail lesion inhibition of each -tes-t compound is sho~n in ~able 2~
~3) ~f~ect on mice in~ec-ted with in~luenza virus Groups9 each consisting of 10 ICR ~emale mice weighing about 25 gO were challenged by intralation of neblyzed influen~a virus A/PR-8. A solu-tion of each test compound in an aqueous solution containing a sur~actant was intraperitoneally administered to the mice 24 hours and 3 hours before the virus in~ection9 and 5 times every other day ~rom the second day after the infectionO ~he mice that survived 21 days a~ter -the challenge were regarded as survivors9 and survival rate was obtained according -to the following equationO
Number of survivors x 100 -- survival rate ~%) ~umber o~ mice treated 3~3~
o o a~
h ~-~
~ ~ O
o a H N t~
, ~ P
P~ ~ r~
.
o o~
0 ~i b ~ l o o ~rl Q~ a ,9 a td ~
~rl ~i C~l O o ~
h o O
g 0~ r-CO
~rl ~rl ~ t) ~i ~1 F4 ~.~
,_ ~ ~ O O
~q . ~ LS~
O r~ ~L
.
a~
1'' 8 O t ~ ~ p~
E~ ~ o ~ } g ~ 10 -3~
oxlcity In order to investiga-te acute -toxicity of tha compounds of the presen-t invention~ 50~0 lethal dose of each compound was ob-tained by using ddY male mice weighing 20 ~ 25 g. From the resul-ts shown in rl'able 37 i-t is understood that -the compounds had high safe-ty margin by in-traperi-toneal administrationO
~able 50~ ~ethal dose ~m ~ ~
Intravenously Intraperitoneally ~est com~ound administered administered N-~hydroxyethyl~i\T'- 150 ~500 solanesylpiperazine As is clear from the foregoing test results 9 the active ingredients of the present invention have interferon inducing activity in vivo and are low in toxicity with showing excellent antivixal activity. In the light of the fact tha-t the s-tric-t correlation of interleron activity with the individual antiviral ac-tivities is not always observed for the present ingredients 9 there is considered also a possibili-ty that the antivirus activities of said ingredients a-t biological level are concerned not only in int~rferon but also in other defensive mechanism of hos-t. 1'here are known various human diseases caused by virus 9 such as herpes-in~ecl;ed diseases (e.g~ herpes simplex)7 influenza7 measles and 1;he like. Accordingly) when the active ingredients of the present invention are used for 3~
prevention ancl treatment of viru,s--infected diseases9 they are adminis-tered to patien-ts by such -techniques involving oral 9 inhalant 9 or the like adminis-tration as well as subcu-taneous 3 intramascular and in-travenous injecti.onO
According to the condition of patient such as age 9 syrQp-tom and rou-te by which the ingredieYl-t is adminls-tered7 the acti~e ingredien-t of the presen-t invention is used in a dose of 0~5 - 20 mg/kg 9 pre~erably 3 - 5 mg/kg several -times (2 - 4 times) per dayO
~he active ingredients of the present invention can be for-mula-ted into composi-tions for medication5 for example 9 table-ts9 capsules9 granules 9 powder9 liquid prepara-tion for oral use9 eye lotions9 suppositories 9 ointments 7 in jections and the like9 according to any conventional method~
~ hen the present active ing-redients are orally administered9 they may be formulated into tablets 7 capsules9 granules ox powderO ~hese solid preparations for oral use may con-tain commonly used excipients9 for example9 silicic anhydride9 metasilicic acid9 magnesium alginate9 s~yn-thetic aluminum silicate 9 lactose9 cane sugar9 corn starch9 microcrystalline cellulose9 hydroxy-propylated starch or glycine9 and the like 9 binders9 for example 9 gum arabic9 gelatin9 tragacanth9 hydroxypropyl cellulose or polyvinylpyrrolidone 9 lubricants9 for example9 magnesium steara-te 9 talc or silica9 disintegrating agents9 for example 9 potato starch and calcium carboxymethyl cellulose; or wetting agen-ts9 for example9 polye-thylene glycol9 sorbitan monooleate9 polyoxyethylene-hardened castor oil9 sodium laurylsulfateO In preparing soft ~3~3~
capsules9 in particular 9 t:he present active ingredien-ts may be formula-ted 'by dissolving or suspending them in polyethylene glyc.ol or common:ly used oily su'bs-tra-tes such as sesame oil 9 peanu-t oil9 gexm oil9 frac-tiona-ted coconut oil such as Miglyol ~ 9 or the like. Tabl~t or granule prepara-tion~ may 'be coated acc.orcling -to the usucll me-thod.
'Li.quid prepaxation for oral use may 'be in the ~orm o~ aqueous or oily emulsi.on or syrup9 or alter natively l~l the form of dry product which can be re-dissolved before use by means o~ a suita'ble vehicle~
~o these liquid preparations 7 there may be added commonly used additives9 for example 7 emulsi~ying aids such a,s sorbitol syrup9 methyl cellulose9 gelatin9 hydroxyethyl cellulose and the like9 or emulsi~iers9 ~or e~ample9 leci-'chin9 sorbitan monooleate9 polyoxyethylene hardened castor oil9 non~aqueous vehicles9 ~or example 9 fractionated coconu-t oil9 almond oil9 peanut oil and the like9 or antiseptics9 for e~ample me-thyl p~hydroxybenzoate9 propyl p~hydroxybenzoate or sorbic acidO ~ur-ther9 these prepara~
~0 tions f'or oral use may contain9 i~ necessary9 preservatives9 s-tabilizers and the like additivesO
In case where the present ac-tive ingredients are administered in the form of non~oral suppository9 they may be formulated according to the ordinary method using oleophi.lic substrates such as cacao oil or Witepsol ~ 9 or may be used in -the form o~ rectum capsule obtained by wrapping a mixture o~ polyethylene glycol9 sesame oil9 peanu-t oil9 germ oil9 fractionated coconut oil and the like in a gelatin sheet. ~he rectum capsule may be coated9 if necessary9 with waxy materials~
- l3 L 3~D
~ en the present active ingredien-ts are used in the form of injection9 -they may be formulated into prepara-tiol~s of oil solution7 emulsl~ied solution or aqueous solution9 and these solutions may contain commonly used emulsi~iers 9 s tabilizers or -the like additi~es.
Accorcling tc the met;hod of administra-tion9 the above-men-tioned compositions can con-tain the presen-t ac-tive ingredients in an amount o~ at least 1~o7 preferably 5 to 50~0 ~ he procedure of formulating -the present active ingredients into various preparations is illus-trated below with reference to Pharmaceutical :Exanples.
Pharmaceutical Example 1 Eard capsule preparations for oral use A mixture of 25 gO of N~~hydroxyethyl~N'~
solanesylpiperazine and 7.5 gO of pol~oxyethylene castor oil in acetone was mixed with 25 gO of silicic anhydride.
A~-ter evaporation of -the acetone 9 the mixture was mixed further with 5 g. of calcium carboæ~methylcellulose 9 5 gO
of corn starchg 705 gO of hydroxypropylcellulose and 20 gO
of microcrystalline cellulose 3 and 30 ml of water was added -there-to and kneaded to give a granular massO ~he mass was pelletized by means of a pelletizer (EC~ pelletter 25 o~ ~u ji Paudal ~o~7 Japan) equipped with l~o. 24 mesh (B.S.) screen to obtain granules. ~he granules were dried to less -than 5~o moisture content and screened with No. 16 mesh (B~S.) screenO ~he screene~ granules were capsuled by means of a capsule filling machine so as -to be contained in an amoun-t of 190 mg per capsule.
L .-3~
Pharmaceutical ~xample 2 Soft capsule preparationsfor oral use A homogeneous solution was prepared by mixing 50 g~ o~ N solanesylpiperazine dihydrochloride with 1~0 g.
of polyethylene glycol (Macrogol ~00). Separately9 a gela-tin solution was prepa~ecl which contained 93 g. o~
gelatin9 19 g. of` glycerine9 10 g. o~ D-sorbitol7 0.4 g, o~ ethyl p--hydroxybenzoate 9 Oo 2 gO of propyl p-hydroxy benzoa-te and 0.4 g. o~ titanium oxide and w.hich wa,s used as a capsule ~ilm ~oxmlng agent. ~he prs~iously ob-tained solution9 together with -the capsule film ~orming agentp was trea-ted with a manual -type ~la-t punching machine to obtain so~t capsules each having the contents of 180 mg.
Pharmaceutical Example 3 Injections A mixture of 5 gO of N~hydroxyethyl~N'~
solanesylpiperazine9 an appropriate amount of peanut oil and 1 g. o~ benzy.l alcohol was made a total volume of 100 cc by addition of peanut oil. The solution was portionwise poured in ~l amount of 1 cc under asepsis operation into an ampule which was then sealed.
Pharmaceutical Example 4 Injections A mi~ture o~ loO g. of N--solanesylpiperazine dihydrochloxide9 5.0 g. o~ Nikkol HC0-60 (a tradename) (hydrogenated castor oil polyoxyethylene--60 mols~ether)9 20 gO o~ propylene glycol, 10 g. o~ glycerol and 5.0 g.
of ethyl alcohQl was mlxed with 100 ml o~ distillsd wate~
and s-tirred. Under asepsis operation~ the solution was portionwise poured in an amolmt of 1.4 ml into an ampule which was then sealed.
Claims (22)
1. A process for the preparation of the nonapreny-lamine derivatives having the general formula:
(I) wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the group R being unsubstituted or substituted with a hydrogen atom or a hydroxy lower alkyl group when it contains an addi-tional nitrogen atom as the further hetero atom, and the pharmaceutically acceptable acid addition salts thereof, which comprises:
a) converting nonaprenol of the formula:
(II) into a corresponding halide or aryl sulfonic acid ester which is thereafter reacted with a heterocyclic compound containing at least one secondary amino group and having the general formula:
(III) wherein R has the aforesaid meaning, in the presence or absence of a base, to obtain the desired nonaprenylamine of the formula (I); and b) when a pharmaceutically acceptable acid addi-tion salt is desired, further reacting the nonaprenylamine derivative of the formula (I) thus obtained with a pharma-ceutically acceptable acid to provide the desired salt.
(I) wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the group R being unsubstituted or substituted with a hydrogen atom or a hydroxy lower alkyl group when it contains an addi-tional nitrogen atom as the further hetero atom, and the pharmaceutically acceptable acid addition salts thereof, which comprises:
a) converting nonaprenol of the formula:
(II) into a corresponding halide or aryl sulfonic acid ester which is thereafter reacted with a heterocyclic compound containing at least one secondary amino group and having the general formula:
(III) wherein R has the aforesaid meaning, in the presence or absence of a base, to obtain the desired nonaprenylamine of the formula (I); and b) when a pharmaceutically acceptable acid addi-tion salt is desired, further reacting the nonaprenylamine derivative of the formula (I) thus obtained with a pharma-ceutically acceptable acid to provide the desired salt.
2. A process according to claim 1, for the preparation of N-solanesylpiperazine, wherein use is made of piperazine as said heterocyclic compound of formula (III).
3. A process according to claim 2, wherein the N-solanesylpiperazine thus obtained is reacted with hydrochloric acid to obtain the corresponding dihydrochloride salt.
4. A process according to claim 1, for the preparation of N-solanesylpiperidine, wherein use is made of piperidine as said heterocyclic compound of formula (III).
5. A process according to claim 4, wherein the N-solanesylpiperidine thus obtained is reacted with hydro-chloric acid to obtain the corresponding hydrochloride salt.
6. A process according to claim 1, for the preparation of N-solanesylmorpholine, wherein use is made of morpholine as said heterocyclic compound of formula (III).
7. A process according to claim 6, wherein the N-solanesylmorpholine thus obtained is reacted with hydro-chloric acid to obtain the corresponding hydrochloride salt.
8. A process according to claim 1, for the preparation of N-solanesylthiazolidine, wherein use is made of of thiazolidine as said heterocyclic compound of formula (III).
9. A process according to claim 8, wherein the N-solanesylthiazolidine thus obtained is reacted with hydro-chloric acid to obtain the corresponding hydrochloric salt.
10. A process according to claim 1, for the preparation of N-solanesylimidazole, wherein use is made of imidazole as said heterocyclic compound of formula (III).
11. A process according to claim 1, for the preparation of N-(.beta.-hydroxyethyl)-N'-solanesylpiperazine, wherein use is made of N-(.beta.-hydroxyethyl)-piperazine as said heterocyclic compound of formula (III).
12. The nonaprenylamine derivatives having the general formula:
(I) wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the group R being unsubstituted or substituted with a hydrogen atom or a hydroxy lower alkyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to claim 1 or its obvious chemical equivalents.
(I) wherein R is a group capable of forming, together with the adjacent nitrogen atom, a 5- or 6-membered heterocyclic ring which may contain a further hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, the group R being unsubstituted or substituted with a hydrogen atom or a hydroxy lower alkyl group when it contains an additional nitrogen atom as the further hetero atom, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to claim 1 or its obvious chemical equivalents.
13. N-Solanesylpiperazine whenever prepared by a process according to claim 2 or its obvious chemical equivalents.
14. N-Solanesylpiperazine dihydrochloride whenever prepared by a process according to claim 3 or its obvious chemical equivalents.
15. N-Solanesylpiperidine whenever prepared by a process according to claim 4 or its obvious chemical equivalents.
16. N-Solanesylpiperidine hydrochloride whenever prepared by a process according to claim 5 or its obvious chemical equivalents.
17. N-Solanesylmorpholine whenever prepared by a process accoxding to claim 6 or its obvious chemical equivalents.
18. N-Solanesylmorpholine hydrochloride whenever prepared by a process according to claim 7 or its obvious chemical equivalents.
19. N-Solanesylthiazolidine whenever prepared by a process according to claim 8 or its obvious chemical equivalents.
20. N-Solanesylthiazolidine hydrochloride whenever prepared by a process according to claim 9 or its obvious chemical equivalents.
21. N-Solanesylimidazole whenever prepared by a process according to claim 10 or its obvious chemical equivalents.
22. N-(.beta.-Hydroxyethyl)-N'-solanesylpiperazine whenever prepared by a process according to claim 11 or its obvious chemical equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55108/1980 | 1980-04-23 | ||
| JP5510880A JPS56150068A (en) | 1980-04-23 | 1980-04-23 | Nonaprenylamine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1183136A true CA1183136A (en) | 1985-02-26 |
Family
ID=12989550
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000376058A Expired CA1183136A (en) | 1980-04-23 | 1981-04-23 | Nonaprenylamine derivatives |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US4755601A (en) |
| JP (1) | JPS56150068A (en) |
| CA (1) | CA1183136A (en) |
| DE (1) | DE3116250A1 (en) |
| FR (1) | FR2481281A1 (en) |
| GB (1) | GB2076395B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4468458A (en) * | 1980-01-12 | 1984-08-28 | Eisai Co., Ltd. | Two-functional-group-containing terpenoids, processes for the preparation of the same, and anti-ulcer agents containing the same |
| JPS56150068A (en) * | 1980-04-23 | 1981-11-20 | Nisshin Flour Milling Co Ltd | Nonaprenylamine derivative |
| AU5522498A (en) * | 1996-12-13 | 1998-07-03 | Merck & Co., Inc. | Substituted aryl piperazines as modulators of chemokine receptor activity |
| JP2018199665A (en) * | 2017-01-26 | 2018-12-20 | 東ソー株式会社 | Alkanolamine, friction reduction agent, and lubricant composition |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2590126A (en) * | 1948-03-10 | 1952-03-25 | Searle & Co | Quaternary ammonium salts of 2, 6-lupetidine |
| BE520888A (en) * | 1952-06-26 | |||
| US3268524A (en) * | 1961-02-20 | 1966-08-23 | Cumberland Chemical Corp | Process for the preparation of amines of the acetylenic series |
| US3268583A (en) * | 1961-02-20 | 1966-08-23 | Cumberland Chemical Corp | Acetylenic amides |
| US3232949A (en) * | 1961-10-12 | 1966-02-01 | Eastman Kodak Co | Process of manufacturing branchedchain mono-olefinic aliphatic acids and intermediates therefor |
| GB1403851A (en) * | 1973-01-03 | 1975-08-28 | Pierrel Spa | Isoprenoid amines |
| US4221810A (en) * | 1978-03-23 | 1980-09-09 | Nisshin Flour Milling Co., Ltd. | Antiulcer compounds |
| CA1147752A (en) * | 1979-05-04 | 1983-06-07 | Yoshiyuki Tahara | Isoprenylamines |
| JPS5673072A (en) * | 1979-11-19 | 1981-06-17 | Nisshin Flour Milling Co Ltd | Decaprenylamine derivative |
| JPS5673046A (en) * | 1979-11-19 | 1981-06-17 | Nisshin Flour Milling Co Ltd | Decaprenylamine derivative |
| US4271810A (en) * | 1980-01-11 | 1981-06-09 | General Motors Corporation | Divided chamber engine with prechamber exhaust recirculation |
| US4324910A (en) * | 1980-02-04 | 1982-04-13 | Pennwalt Corporation | Substituted urea compound containing 2,2,2-trichloro-1-hydroxyethyl group |
| JPS56150068A (en) * | 1980-04-23 | 1981-11-20 | Nisshin Flour Milling Co Ltd | Nonaprenylamine derivative |
| GB2079395A (en) * | 1980-06-27 | 1982-01-20 | British Aluminium Co Ltd | Clamp joint for panels |
-
1980
- 1980-04-23 JP JP5510880A patent/JPS56150068A/en active Granted
-
1981
- 1981-04-22 US US06/256,579 patent/US4755601A/en not_active Expired - Fee Related
- 1981-04-23 DE DE19813116250 patent/DE3116250A1/en active Granted
- 1981-04-23 CA CA000376058A patent/CA1183136A/en not_active Expired
- 1981-04-23 GB GB8112603A patent/GB2076395B/en not_active Expired
- 1981-04-23 FR FR8108137A patent/FR2481281A1/en active Granted
-
1988
- 1988-04-07 US US07/178,510 patent/US4857529A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| GB2076395B (en) | 1984-03-07 |
| FR2481281A1 (en) | 1981-10-30 |
| US4755601A (en) | 1988-07-05 |
| DE3116250C2 (en) | 1988-12-22 |
| GB2076395A (en) | 1981-12-02 |
| JPH0132826B2 (en) | 1989-07-10 |
| DE3116250A1 (en) | 1982-04-01 |
| JPS56150068A (en) | 1981-11-20 |
| FR2481281B1 (en) | 1984-02-17 |
| US4857529A (en) | 1989-08-15 |
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